There are thousands of leucine-rich repeat (LRR)–containing proteins, which share a common structural horseshoe-shaped motif but have distinct and unrelated functions. Among the LRR-containing proteins involved in the immune system, Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)–like receptor proteins (NLRPs) easily come to mind, with important functions in pathogen recognition by innate immune cells. Nevertheless, there are many other LRR-containing proteins whose functions remain to be fully elucidated.

In this issue, Kumar et al. report their work on the role of LRRC8A in lymphocyte development and function. The current study was initiated following identification of a translocation mutation in the LRR-containing 8A (LRRC8A) gene in a patient with no B cells and agammaglobulinemia, which resulted in a truncated protein that severely inhibited B cell development and function. However, the function of LRRC8A in lymphocytes or its role in other cell lineages is not fully understood.

The authors generated Lrrc8a-deficient mice that showed a defect in both T cell development and function, with increased thymocyte apoptosis, but only a mild defect in B cell development. LRRC8A, which is expressed on the cell surface, appears to engage a ligand expressed on thymic epithelial cells, as well as on multiple other stromal cells. The authors provide evidence that this interaction leads to AKT activation via an LCK–ZAP-70–GAB2–PI3K signaling pathway in T cells. However, further work will be required to definitively establish whether the AKT signaling pathway is crucial for the defect in thymocyte development observed in Lrrc8a-null mice. In addition to the defect in thymocyte survival and proliferation, Lrrc8a-deficient mice also exhibited defective T cell function downstream of the TCR. These findings were unexpected, as the initial characterization of the human LRRC8A mutation had a more severe defect in the development and function of B cells than T cells. This difference may be due to a dominant-negative gain of function of the truncated mutation displaying broader and distinct effects in humans compared with the effects observed in the gene-deficient mice.

These exciting findings point to an as yet unappreciated role for LRR-containing proteins in T cell development and function. It is likely that other members of this large gene family may be equally important, and thus the present report serves as a clarion call for further work on LRRC8A-related genes in lymphocyte differentiation and function.

et al
J. Exp. Med.